Abstract Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that causes progressive neurological deficits, which affects 400,000 people in the USA. This incurable, life-long disease is quite costly to the health care system and society with a conservative estimate of a national annual cost of $20 billion in 2007. The prevalence and incidence of MS are increasing worldwide. Thus, the need for strategies to prevent MS is greater than ever. The cause of MS remains unknown; it is generally accepted that the combination of genetic and environmental factors determines the disease susceptibility. Vitamin D deficiency is emerging as an important environmental risk of MS. Epidemiological studies have shown that MS frequency increases with higher latitude, which is inversely correlated with sunlight and vitamin D levels. Furthermore, studies of migration and sun exposure indicate susceptibility to develop MS is determined in childhood, although disease onset is later in life. Providing sufficient vitamin D in early life may be beneficial to prevent MS. What is not known is how early life vitamin D deficiency influences the susceptibility to adult-onset MS. No studies have investigated whether low vitamin D during early life enhances the risk of developing autoimmune demyelinating disease in adulthood. Vitamin D receptors are prevalent in both the immune system and central nervous system (CNS), making both systems potentially altered due to low vitamin D during early life. MS is the autoimmune disease most closely linked to sunlight/vitamin D levels suggesting that there is a CNS-specific component related to vitamin D signals that may contribute to the risk of developing MS. The longterm goal of this study is to understand the mechanism by which sufficient vitamin D in early life imprints the protection against MS development later in life. The overall objective of the proposed project is to compare the susceptibility of mice to EAE in which there is impaired vitamin D signaling in the immune system or CNS during early life. Our main hypothesis is that reduced vitamin D signaling during early life makes the CNS more vulnerable to inflammation, enhancing the susceptibility to autoimmune demyelinating disease. The rationale that underlies this study is that, once the correlation of early life vitamin D deficiency and MS susceptibility is fully defined, this will be the foundation for making a public health policy to manipulate this easily modifiable risk factor for MS. The specific aims are as follows: 1) determine if vitamin D insufficiency in the immune system in juvenile mice enhances susceptibility to EAE, and 2) determine if vitamin D insufficiency in the CNS in juvenile mice enhances susceptibility to EAE. The relative contribution of vitamin D signaling in the immune system versus the CNS is necessary to understand the role that vitamin D plays in MS risk, and how the data may be applicable to other autoimmune diseases and neurodegenerative diseases. Understanding how this environmental factor influence MS risks will be a significant step towards the ultimate goal - preventing MS.